Transgenic mouse models offer great promise for both defining the pathological mechanisms of Alzheimer's Disease (AD) and assisting in the development of effective therapies. The Tg2576 line of transgenic mice (Hsiao et al., 1996) demonstrates an important number of pathological features that reveal a striking correspondence to human AD, including the region-specific, age-dependent elevation of Abeta levels (both the 1-40 and 1-42/43 isoforms) and development of dense-core amyloid plaques. Perhaps most importantly, the Tg2576 mice also showed deficits in performance on learning and memory tasks, at the same age at which they demonstrated explosive increases in neuropathological symptoms. Moreover, our preliminary data indicate that the behavioral deficits were correlated with the development of abnormalities in long-term synaptic plasticity. We propose to extend our knowledge of the behavioral and physiological phenotype of the Tg2576 mouse. We have developed a focused set of behavioral tests. These behavioral tests will also allow us to test mice frequently and at regular intervals, so that we will develop a better understanding of not only the nature of the behavioral phenotype, but also the time-course of its development. At the same time, we will examine in detail the synaptic physiology of the Tg2576 mice, both in vitro and in vivo. As we learn more about the behavioral and physiological phenotype, including the developmental time-course of each, we ill be in a better position to document and understand the correlation between synaptic physiology, behavior, and neuropathology.